Antiviral compounds and methods of use thereof
Inventors
GUENTHER, Richard H. • Sternbach, Daniel • Peterson, Steven E.
Assignees
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Publication Number
US-9877956-B2
Publication Date
2018-01-30
Expiration Date
Abstract
Inhibitors of retroviral propagation, methods of treatment and prevention of retroviral infections using the inhibitors, and pharmaceutical compositions including the inhibitors, are disclosed.
Core Innovation
The invention relates to retroviral propagation inhibitor compounds, including compounds of Formula II and pharmaceutically acceptable salts thereof, for treating or preventing a retroviral or HIV infection. The disclosed framework defines structural parameters using substituents R1, R2, R3, R4, and X, where X is O or S, with specific allowable choices for hydrogen, C1-6 alkyl, C1-6 haloalkyl, and halo substituent selections.
The described inhibitors are characterized as blocking multiple steps in retroviral lifecycle processes. The disclosed mechanism includes inhibition of reverse transcription, viral primer recruitment involving tRNA Lys3 interactions, host cell tRNA binding to target nucleic acid, and late-stage virion packaging and assembly of newly formed virions. In this way, the compounds are presented as multi-step retroviral propagation inhibitors rather than inhibitors restricted to a single lifecycle event.
The disclosure also describes screening concepts using tRNA anticodon stem-loop fragments and labeled target RNAs, together with assays such as immobilized binding and AlphaScreen. Example lead hits, including Trana 154 and Trana 156, are described with reported antiviral activity in PBMC and cytotoxicity metrics, and the disclosure further supports treatment and prevention approaches, including combination therapy and pharmaceutical compositions.
Claims Coverage
The independent claim covers a method of treating or preventing a retroviral or HIV infection by administering an inhibitor of retroviral propagation where the inhibitor is a compound of Formula II or a pharmaceutically acceptable salt. The coverage includes multiple dependent inventive features that specify inhibited lifecycle steps and support combination and virus-variant selection with additional antiviral agent co-administration.
Formula II propagation inhibitor for treating or preventing HIV infection
Administering an inhibitor of retroviral propagation that is a compound of Formula II, where R1 is hydrogen or C1-6 alkyl, R2 is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and halo, R3 and R4 are independently hydrogen and C1-6 alkyl, X is O or S, and the inhibitor is provided as pharmaceutically acceptable salts thereof.
Inhibition of retroviral reverse transcription
The inhibitor inhibits retroviral reverse transcription.
Blocking viral primer recruitment involving human tRNA Lys3
An inhibitor blocks viral recruitment of the retroviral primer used in translation, specifically human tRNA Lys3.
Inhibition of final packaging and assembly of newly formed virions
An inhibitor blocks the final packaging and assembly of newly formed virions.
Co-administration of a second anti-HIV compound
The method further includes co-administering a second anti-HIV compound.
Virus selection among HIV variants or mutated versions
The HIV used is selected from HIV-I, HIV-II, HIV-III, or mutated versions thereof.
Overall, the claims coverage centers on administering a Formula II retroviral propagation inhibitor for treating or preventing HIV infection, with dependent refinements that specify inhibition of reverse transcription, primer recruitment involving human tRNA Lys3, late-stage final packaging and assembly of newly formed virions, and treatment regimens that include co-administration of a second anti-HIV compound and selection of HIV variants or mutated versions.
Stated Advantages
Inhibits multiple retroviral lifecycle steps, including reverse transcription, primer recruitment involving tRNA Lys3 interactions, host cell tRNA binding to target nucleic acid, and virion packaging and assembly.
Provides antiviral activity in PBMC while reporting cytotoxicity metrics for disclosed lead hits.
Documented Applications
Treatment or prevention of a retroviral infection described as an HIV infection by administering a retroviral propagation inhibitor compound of Formula II and pharmaceutically acceptable salts.
Combination therapy approaches through methods that further include co-administering a second anti-HIV compound.
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